DESCRIPTION: The principal objective of this research is the development and application of new methods and synthetic strategies for the preparation of macrocyclic ansa compounds exhibiting mechanistically unique antitumor and antiviral properties. It is stated that targets of the program include herbimycin A, geldanamycin and members of the ansatrienin family of ansamycins, including mycotrienol I and ansatrienin A. It is reported that the antiproliferative activity of the benzoquinoid ansamycins stems from their inhibitory action against receptor and non-receptor protein tyrosine kinases (PTKs), an observation with significant implications for efforts to develop antitumor and antiviral strategies and for investigations of the intracellular events surrounding cell growth and differentiation. The PI notes that tyrosine kinases have been identified as oncogenic products of transforming retroviruses and appear at elevated levels in a number of malignant cell types and that the implication of PTKs as causative factors in pathological states resulting from uncontrolled cell proliferation presents a strategic molecular opportunity for antitumor and antiviral chemotherapy. A long range goal of the program is the development of a comprehensive strategy for the synthesis of polyketide-derived arrays based on serial application of diastereoselective sigmatropic rearrangements. The PI notes that his approach to the benzoquinoid ansamycins, based on linear development of the polyketide-derived ansa system by serial application of the (2,3) Wittig and other diastereoselective sigmatropic rearrangements, is broadly relevant to the synthesis of polyketide natural products, including the immunomodulators rapamycin and discodermolide. He indicates that he will carry out investigations of new sigmatropic methodology addressing specific structural and stereochemical elements of polyketide-derived natural products and examine new substrates for the chelation-mediated (2,3) Wittig rearrangement of allylic ethers.